Objective To assess the additional cost of treating cancer patients in the National
Cancer Institute (NCI)–sponsored clinical trials in the United States
across a range of trial phases, treatment modalities, and patient care settings.

Design Retrospective cost study using a multistage, stratified, random sample
of patients enrolled in 1 of 35 active phase 3 trials or phase 1 or any phase
2 trials between October 1, 1998, and December 31, 1999. Unadjusted and adjusted
costs were compared and related to trial phase, institution type, and vital
status.

Setting and Participants A representative sample of 932 cancer patients enrolled in nonpediatric,
NCI-sponsored clinical trials and 696 nonparticipants with a similar stage
of disease not enrolled in a research protocol from 83 cancer clinical research
institutions across the United States.

Main Outcome Measures Direct treatment costs as measured using a combination of medical records,
telephone survey, and Medicare claims data. Administrative and other research
costs were excluded.

Conclusions Treatment costs for nonpediatric clinical trial participants are on
average 6.5% higher than what they would be if patients did not enroll. This
implies total incremental treatment costs for NCI–sponsored trials of
$16 million in 1999. Incremental costs were higher for patients who died and
who were in early phase studies although these findings deserve further scrutiny.
Overall, the additional treatment costs of an open reimbursement policy for
government-sponsored cancer clinical trials appear minimal.

Figures in this Article

The cost of conducting cancer clinical trials has traditionally been
supported by a combination of research sponsors, institutions, and third-party
payers. However, private health insurance plans are frequently reluctant to
reimburse for direct patient care provided as part of a clinical trial.1 This reluctance, driven in part by a perception that
patients enrolled in trials incur substantial additional costs,2,3 impedes
efforts to enroll patients in trials.4 Yet
there is a lack of generalizable evidence regarding the costs of treating
patients in clinical trials. Given the importance of clinical research in
identifying better treatments,5- 9 there
is a need for precise estimates of the additional treatment costs associated
with trial participation.

Although some private insurance companies reimburse routine costs—ie,
care that would have been received in the absence of trial participation—the
policy is far from universal and often is not made explicit.4 Medicare
is a notable exception, having agreed to cover treatment for trial participants
in the year 2000. For those private insurance companies that do reimburse
routine costs, the ambiguity of what is covered invites conflict, and this
uncertainty must be disclosed during the informed consent process.10 The result is to discourage enrollment by patients
and participation by health care professionals. Better information about the
incremental costs of trial participation over standard care could lead to
more universal and consistent coverage policies for clinical research.

Several studies have investigated the costs of care within cancer clinical
trials and generally have found cost differences of between 0% and 10% for
patients in National Cancer Institute (NCI)–sponsored trials compared
with matched controls (W. Barlow, written communication, August 1999).11- 15 Part
of the problem is that these findings reflect different treatment patterns,
for each of these studies was conducted at major research institutions or
specialized health maintenance organizations, which may have engaged in a
nonrepresentative set of clinical trials. The additional costs of trial enrollment
may also be different in community settings where most patients receive care.
More generalizable data are needed to convince insurers and policymakers,
and this has led to calls for additional estimates.16 The
Cost of Cancer Treatment Study (CCTS) was designed to address this need by
providing a point estimate for the additional costs of trial enrollment across
a range of trial phases, treatment modalities, and patient care settings.

METHODS

Sampling

As described elsewhere,17 the CCTS is
a retrospective cohort study of a representative sample of clinical trial
participants and matched nonparticipants. The sample sizes were chosen to
detect a 10% difference in costs with a .80 power at a .05 significance level.
This choice was made after private consultation with executives at 4 major
private insurance companies who noted that estimates below this amount would
be helpful in making informed decisions about whether to provide greater access
to trial enrollment.

Using data on all nonpediatric phase 3 treatment trials supplied by
the Cancer Therapy and Evaluation Program at the NCI, we randomly sampled
35 of 92 active clinical trials with probability of selection proportional
to actual patient accrual from October 1, 1998, to March 31, 1999. The selected
trials represented 66% of phase 3 accrual. The clinical investigation of experimental
drugs is normally conducted in 3 phases. Phase 1 trials (to determine safety)
and phase 2 studies (to determine efficacy) involve at most a few hundred
patients and are short in duration. In contrast, phase 3 studies test the
overall benefit and risk profile of an experimental drug, involve several
hundred to several thousand patients, and typically last several years. We
then compiled a list of all clinical sites (n = 432) affiliated with these
phase 3 trials and randomly sampled 55 study sites, again with probability
proportional to accrual.18 Each study site
consisted of a multicenter program with a core institution and affiliates.
Of the 148 institutions we approached, 83 agreed to participate. Participating
sites accounted for 63% of overall trial accrual from all sites selected for
our sample.

Trial Participants. At each institution, patients
were eligible for our study if they enrolled in 1 of our 35 sampled phase
3 trials or any phase 1 or phase 2 trial between October 1, 1998, and December
31, 1999. Phase 1 and 2 trials were not restricted to a random sample because
there were fewer of them, accrual was much lower than what it was for the
phase 3 trials, and in some cases, accrual data were unavailable. At each
institution, we identified a site captain (often a clinical trials coordinating
nurse) who located eligible patients and obtained contact information. Of
the trial participants contacted by the site captains, 61% enrolled in the
CCTS (n = 777). Table 1 provides
a summary of sample sizes and Figure 1 provides
a study flow chart.

Figure. Study Flow Chart

Nontrial Participants. Nonparticipants for
the CCTS were adult patients who met the eligibility criteria for 1 of our
trials but who did not receive therapy as part of any clinical trial (Table 2). For each CCTS trial participant,
site captains attempted to enroll a matched nonparticipant at the same institution.
Site captains identified eligible patients through tumor registries or other
administrative data followed by a brief medical record screen, which is an
efficient method for identifying cancer patients meeting an abbreviated set
of trial entry criteria.19 When nonparticipants
were unavailable, we sought a nonparticipant with similar clinical characteristics
at a different member institution. Enrollment rates were slightly lower for
nonparticipants (56%) than for trial participants (61%). All trial participants
and nonparticipants enrolled in the CCTS through contact with site captains
were alive. Enrollment of deceased trial participants and nonparticipants
is discussed below.

Data Sources

Telephone Survey. Recognizing that some patients
might receive care from multiple practitioners, we used a telephone survey
to obtain the names of all of the physicians whom patients had seen since
their cancer diagnosis or since January 1, 1998, if the diagnosis date was
earlier. The survey also elicited information on demographics, attitudes toward
care, insurance coverage, health status, and comorbidities. Survey respondents
also were asked to enumerate physician office visits, home care visits, inpatient
stays, and lengths of stay for each practitioner over the preceding 6 months.

Medical Records. Medical records were requested
from all inpatient and outpatient practitioners identified in the survey and
abstracted to obtain information on utilization. We defined an observation
window as the period over which we observed all utilization and costs, starting
from the date of diagnosis. We used date of diagnosis for trial participants
rather than the date of trial enrollment for 3 reasons: (1) the 2 correspond
very closely; (2) the date of diagnosis provides an analogous index date for
the nonparticipant patients not enrolled in clinical trials; and (3) some
services received prior to trial enrollment could be associated with the trial
(eg, clinical examinations and laboratory tests to determine protocol eligibility).
For some patients, diagnosis was later or practitioners submitted medical
records earlier in the study, making the observation period shorter. This
period averaged 2.5 years (SD, 7.5 months) but varied across patients. The
mean period of observation for living patients was 28.7 months for trial participants
and 29.9 months for nonparticipants. Corresponding periods for deceased patients
were 34.1 and 33.1 months, respectively.

Trained nurse abstractors abstracted 4032 medical records using computerized
forms developed for this study. Initially, all records were reabstracted by
a quality control supervisor; this rate was reduced to 10% and then 5% over
time as interrater reliability remained in excess of 95%. Abstracted data
included number of physician visits, lengths of stay for inpatient care, and
counts of specified tests and procedures. (A technical appendix with more
detail is available at http://www.rand.org/health/goldman_app.pdf.)
We include all drugs administered in a physician's office, hospital outpatient
department, or chemotherapy setting (technically, any drug reimbursed by Medicare).
Like other studies, we did not include outpatient drugs.11

Deceased. We requested medical record data
for 454 trial participants and nonparticipants who were eligible for the study
but who died before they could be contacted. In some instances, the institutions
provided records, and in others, they obtained consent to provide records
from an executor or family member. We received medical records for 252 deceased
patients.

Medicare Administrative Data. For 437 patients
who were Medicare eligible, we also obtained enrollment and claims data for
1998-2000 from the Centers for Medicare and Medicaid Services as an additional
validation of our results. We excluded 122 patients who were enrolled in a
Medicare health maintenance organization because claims were missing or who
entered Medicare subsequent to diagnosis. For the remaining 315 patients,
we computed total expenses by both Medicare and the patient from the date
of diagnosis.

SEER-Medicare. For our cost imputations, we
used Medicare data from 60 995 patients from the Surveillance, Epidemiology,
and End Results (SEER)–Medicare database, which links Medicare billing
records to tumor registry information for cancer patients registered in the
NCI's SEER program database.20

Cost Measurement

Costs refer to total payments to providers for direct medical care,
which included third-party payments and any expenses that would be the responsibility
of patients. Our primary measure was derived by applying prices (actually
cost weights) developed from the SEER-Medicare database to abstracted medical
record utilization data. To develop the prices, we first adjusted payments
in the SEER-Medicare database to 1998 constant dollars using Medicare time
and geographical adjustment factors for part A and part B.21 We
then identified in the Medicare-SEER data 79 outpatient utilization measures
and 67 inpatient measures that we also abstracted from medical records. For
each hospital admission, we then regressed total cost (in 1998 dollars) on
inpatient utilization measures. Separate regression analyses were performed
for admissions that occurred within 6 months of diagnosis and admissions that
occurred thereafter. For outpatient services, we regressed total outpatient
costs for services after diagnosis on outpatient utilization measures and
binary variables defining the period of treatment after diagnosis. The cost
weights derived from these regression models were then applied to utilization
from the CCTS medical records. More detail, including regression results,
are provided in the technical appendix.

Some living patients had incomplete or no medical record data. For those
with incomplete data, we inflated their costs by simple adjustment for the
number of practitioners. More complicated methods that used the survey data
to adjust for self-reported utilization for each practitioner yielded similar
imputed values. There were also 251 living patients for whom we obtained no
medical records. To impute costs for these patients, we first estimated a
multivariate regression analysis using 1125 living patients with at least
some medical records data. The regression predicted costs as a function of
age, sex, race, educational status, census region of residence, type of cancer,
self-reported comorbidities, and costs from Medicare claims, when available.
We then imputed costs for the 251 missing patients using predictions from
this regression. The results of the study were insensitive to the inclusion
of these patients and the method of imputation (Table 3).

Cost Analysis

We used multivariate regression analyses to compare the costs of trial
participants and nonparticipants. This joint approach—matching combined
with regression adjustment—is preferable to matching alone.18 Medical costs (logarithmically transformed) were
regressed on demographic characteristics, comorbid conditions, prior therapy,
stage, histology, insurance status, and trial status (whether the patient
participated in a trial). Trial status was interacted with phase and whether
the patient was deceased to allow for separate estimates by type of trial
and vital status with phase 1 and phase 2 combined because of the small sample
size. Costs were predicted using consistent retransformation methods that
allow for heteroscedasticity based on quintiles of expected log costs.22

Nonresponse

All cost analyses were weighted to adjust for the sample design, nonresponse,
and possible selection bias between trial participants and nonparticipants.
There were no nonresponding trials in our design, and our institution sample
represented a broad cross-section of cancer practitioners participating in
clinical trials: 34 were academic medical centers, 24 were oncology practices
participating in the NCI's Community Clinical Oncology Programs, and 25 were
other types of institutions, such as private hospitals or providers' offices.
Site captains asked nonrespondents for permission to report patient background
information, including age, sex, race or ethnicity, date and stage of diagnosis,
and date of recent hospitalization. These data were used to construct nonresponse
weights. We poststratified to match all bivariate distributions of phase,
cancer type, and vital status using data from our nonresponse screeners and
the Cancer Therapy and Evaluation Program. The largest effect of these weights
was to downweight breast cancer and phase 3 patients. In addition, we constructed
propensity score weights to accommodate nonrandom assignment between trial
participants and nonparticipants.23

RESULTS

There were 1628 patients enrolled in the CCTS, which comprised 932 trial
participants and 696 nonparticipants (Table
1). We completed 1376 telephone interviews with living patients
to identify all their medical practitioners and were able to obtain at least
1 medical record for 1125: 651 records for trial participants and 474 for
nonparticipants. A total of 4032 records were abstracted for an average of
3.6 records per patient and 71% of all records requested. We also obtained
1 medical record for each of 252 deceased patients. Medicare data were received
for 355 living patients and 82 deceased patients.

Table 2 compares the sample
characteristics. Patients in phase 3 trials are overrepresented because national
data on accrual from the Cancer Therapy and Evaluation Program for 1999 suggest
about 71% of patients enrolled in phase 3, 22% in phase 2, and 7% in phase
1. Our analysis allows for different treatment costs in phase 3 trials, and
our overall estimates were adjusted to reflect the national data. The populations
otherwise look very similar, and there were no significant differences in
comorbidities. Trial participants rarely changed practitioners to enroll in
a trial and did not differ from nonparticipants in their attitudes toward
medical care. Nonparticipants more often have breast cancer, are less likely
to be nonwhite, are more likely to have Medicare coverage, and are older.
They also were diagnosed more recently. Because our statistical approach does
not rely on exact matching, such differences will not induce bias because
we include these characteristics in the multivariate analysis.

Table 3 shows unadjusted
cost differences using alternative samples and sources and measured in 1998
dollars. Our primary measure of costs combines information from the medical
records, Medicare claims, and (occasionally) self-reported utilization as
described above. Participants averaged $33 325 in treatment costs compared
with $32 364 for nonparticipants over the period of observation—typically
30 months. The 3% difference between the 2 groups was not statistically significant.
Cost differences varied substantially within trials, with incremental cost
differences ranging from −30% to 49% among trials with at least 15 study
participants and matched nonparticipants. As a check on these results, we
compared costs from the Medicare claims files for the smaller sample for whom
such data were available. Treatment costs for this sample were 4% less than
nonparticipants. Using the sample of patients with at least some medical record
data suggests trial participants are 4% more expensive. Finally, for those
with complete medical records (ie, patients for whom there was no imputation)
trial participants are 1% less expensive than nonparticipants.

Table 4 shows our main results
using the entire sample and adjusting for possible confounding factors. (Full
regression results are given in Table 4A of the technical appendix.) Overall,
trial participation results in a cost increase of 6.5%. Although the CCTS
was not powered to consider subgroup analyses, some interesting findings do
emerge when the data are analyzed this way. Phase 3 studies had lower cost
differences (3.5%) than the earlier study phases (12.8%). There was not a
large difference in incremental costs between academic health centers (AHCs)
and other care settings. The largest difference was by vital status. Patients
who died during trials incurred much higher costs (17.9%) than nonparticipants
who died, whereas the additional cost of trial participation for patients
who survived was small (3.5%).

Table 5 suggests why trial
participants were more expensive to treat. Trial participants received more
physician visits, more expensive tests (magnetic resonance imaging, computed
tomography, and multiple gated acquisition scans, endoscopies, and nuclear
medicine procedures), and more pathology reports. Much of the increased service
use was for deceased participants, who used significantly more physician visits,
expensive diagnostics, and pathology reports than did deceased nonparticipants.
Overall, nonparticipants had more hospital days, but the difference was not
significant.

COMMENT

Uncertainty about the incremental costs from trial enrollment has led
to uneven policies by insurance companies. Medicare may be the most salient
example. It covers "routine costs" associated with clinical trials. The Institute
of Medicine recently recommended that Medicare should pay for more than routine
costs, at least for selected trials.10 Such
language is standard but invites misinterpretation. The definition of routine
costs can be unclear, and this language encourages clinical researchers to
design research protocols in such a way that the treatment costs will not
exceed standard care by too much. This may explain why the additional treatment
costs from trial participation are so small, but it also may have adverse
consequences for the clinical investigation.

We undertook the CCTS to provide precise and generalizable estimates
of the incremental treatment costs associated with nonpediatric clinical trials
for cancer treatment. We focused on direct costs for patient treatment since
these are the costs that insurance companies might reasonably be asked to
pay in the absence of a trial. Of course, government-sponsored clinical trials
involve other administrative and research costs beyond direct care, including
staff training, trial administration, analysis, and reporting. These costs,
primarily underwritten by the study sponsors, clearly warrant further investigation.24 Our study also excludes industry-sponsored trials,
which have been estimated to enroll roughly the same number of cancer patients
(20 000 to 25 000 annually).25 However,
unlike NCI-sponsored trials, there is no central data repository from which
we could draw a sampling frame for industry-sponsored trials. Furthermore,
there is evidence that industry-sponsored trials cover more of the costs of
treatment, and in fact generate additional income for participating institutions.26,27

Our findings suggest that treatment costs for an adult patient enrolled
in an NCI-sponsored trial are, on average, 6.5% higher over a period of 2.5
years than what they would be if the patient did not enroll in a trial. Much
of the additional cost comes from higher use of physician visits and expensive
diagnostic testing. Fireman et al12 also found
evidence that trial participants had higher rates of ancillary services.

We expected that the CCTS would yield larger differences in costs relative
to others because our study included health care settings outside AHCs. In
fact, we found little difference in incremental treatment costs between AHC
and non-AHC providers, which explains why our results are close to what others
have found in single-institution studies. It is possible that patients may
change institutions to participate in a clinical trial although only 8% of
our trial participants did so. In part, this may reflect the success of the
NCI's Community Clinical Oncology Program, designed to make trials available
in settings where patients already receive their care. Little published evidence
about the nature and scope of such switching exists. Studies of patient characteristics
associated with being offered enrollment in a cancer trial28,29 have
generally been conducted among patients at academic medical centers and have
not examined whether patients had been referred to these institutions from
other providers. Similarly, studies of clinician characteristics associated
with referring cancer patients to clinical trials30- 32 have
focused on clinicians involved in cancer research and/or at AHCs.

We find that the incremental cost is associated with more services,
especially physician visits, expensive tests, and pathology reports. In a
phase 3 study, these services may accrue differentially for patients in the
treatment and control arms. Thus, it is an open question whether patients
in the control arm of a trial actually receive more treatment than the nonparticipants
in the same institution. This also raises the question of whether trial participants
are getting any health benefits for these incremental services. In their review
of the literature, Braunholtz et al,33 found
limited evidence for such a "trial effect."

The type of trial also matters. Patients enrolled in early phase studies
have much higher additional treatment costs compared with those in phase 3.
In part this is due to more aggressive treatment of trial participants in
phase 1 or 2 studies relative to phase 3, but also the higher likelihood that
these patients will die during the study period. Deceased trial participants
in our study had costs that were about 18% more expensive than they would
have incurred had they not enrolled in a study, and early phase trials include
patients with the worst prognoses. This finding appears in other studies;
Wagner et al11 note that trial participants
incurred "substantially higher cost" in the last 3 months of life in their
5-year study at Mayo Clinic, Rochester, Minn. Patients in trials may prefer
more aggressive treatment despite incurable disease. However, we observed
no differences between trial participants and nonparticipants in preferences
for aggressive care, as measured in our survey.

Alternatively, physicians conducting trials may be more aggressive in
trying to save trial participants. The higher costs for deceased trial participants
also could be an artifact of our inability to identify all the clinicians
who served each patient. Survey respondents saw approximately 4 different
practitioners between interview and diagnosis, but we only obtained 1 record
per deceased patient. Undercounting utilization will only bias our results
if it is systematically different between deceased trial participants and
nonparticipants. Based on our telephone survey, trial participants identified
seeing only slightly fewer practitioners than nonparticipants (4.18 vs 4.25,
respectively). Thus, there is little evidence for a systematic bias among
the living respondents.

There is little evidence that our trial participants differ in unobserved
ways from our nonparticipants. As noted, we observed no differences between
trial participants and nonparticipants in attitude toward care, and enrollment
rates were similar across the 2 groups (61% for trial participants; 56% for
nonparticipants). Also, some of our nonparticipants were drawn from institutions
that did not participate in study trials, so our sample does not include only
patients who chose not to participate in a clinical trial. Differential nonresponse
by trial participants and nonparticipants was accounted for in our weighting
scheme using data provided by institutions on nonrespondents.

Our 6.5% estimate can be interpreted as the incremental cost conditional
on a representative set of trials and institutions from 1999. Changes in the
mix of patients enrolling in trials, or the type of trials being conducted,
would likely yield a different result. At the time this study was conducted,
Medicare did not routinely pay for medical care incidental to clinical trials.
This is no longer the case, and Medicare is also considering what level of
inducements would be allowable to encourage trial participation by Medicare
beneficiaries.34 If these inducements were
substantial, the fraction of trial enrollees coming from Medicare could rise.
The question then arises whether the incremental treatment costs vary when
the mix of enrollees changes substantially. Estimates from auxiliary models
(not shown) did not find any significant interactions between payer status
(Medicare) and additional treatment costs, but it is not clear whether this
is due to a different mix of trials for this population or due to different
treatment of Medicare beneficiaries within trials. This is an issue worthy
of future research.

Of equal import, it may be that an open reimbursement policy could result
in greater incremental costs by inducing a behavioral response in the trials
that are undertaken, especially in more aggressive trials. This cost increase
presumes that uncertainties about reimbursement in the status quo limit which
trials are initiated. Putting aside that eliminating this barrier is likely
to accelerate improvements in cancer treatment, it also will result in higher
incremental costs than we report herein. If one assumes that the early phase
studies provide an upper bound—an extreme assumption about how the mix
of trials would change—then the incremental costs would be at most 13%
as shown in Table 4.

Conclusion

In 1999, approximately 19 000 adult patients participated in NCI-sponsored
US clinical trials which, incurred direct treatment costs of approximately
$268 million. These costs would have been $252 million if these patients had
not enrolled in trials, implying that the incremental treatment costs associated
with NCI-sponsored trial enrollment were $16 million. Given that trial participants
represent only about 3% of all adults with cancer and given that the incremental
costs are only 6.5%, the additional treatment costs of an open reimbursement
policy for NCI-sponsored trial participation appear minimal.

Quirk J, Schrag D, Radzyner M.
et al. Clinical trial costs are similar to and may be less than standard care,
and inpatient charges at an academic medical center are similar to major,
minor, and nonteaching hospitals. In: Program and abstracts of annual meeting of the American Society
of Clinical Oncology; May 2000; New Orleans, La.

Stinson TJ, Bennett CL, Vogel V.
et al. A multi-center study of the costs of enrolling cancer patients in phase
II clinical trials. In: program and abstracts of the annual meeting of the American Society
of Clinical Oncology; May 2000; New Orleans, La.

Quirk J, Schrag D, Radzyner M.
et al. Clinical trial costs are similar to and may be less than standard care,
and inpatient charges at an academic medical center are similar to major,
minor, and nonteaching hospitals. In: Program and abstracts of annual meeting of the American Society
of Clinical Oncology; May 2000; New Orleans, La.

Stinson TJ, Bennett CL, Vogel V.
et al. A multi-center study of the costs of enrolling cancer patients in phase
II clinical trials. In: program and abstracts of the annual meeting of the American Society
of Clinical Oncology; May 2000; New Orleans, La.

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